CS260076B1 - Process for the preparation of di-tert-butyldicarbonane - Google Patents

Abstract

Di-tert-butyl dicarbonate of the formula (CH3)3C-0-C0-0-C0-0-C(CH3>3 is prepared by the reaction of benzenesulfonyl chloride or p-toluenesulfonyl chloride with sodium tert-butyl carbonate. The reaction is catalyzed by the addition of pyridine and quaternary ammonium halides, in which one substituent is phenyl, benzyl or alkyl C10-20 and the other three substituents are identical alkyls C1_4<. To a suspension of sodium tert-butyl carbonate in toluene, p-toluenesulfonyl chloride and a solution of quaternary ammonium halides in pyridine are added, the reaction mixture is stirred at 20 to 70 °C for 1 to 7 h and then worked up. The addition of a catalyst achieves a significant acceleration of the reaction and an increase in yield. The obtained substance is used in the chemistry of amino acids and peptides as a protecting agent.

Description

The present invention relates to a process for the preparation of di-tert-butyldicarbonate of the formula I (ch ₃ ) ₃ co-co-o-co-α ₃ ( ₃ ) (I)

It is a modern preservative used, for example, in peptide chemistry, and has significant advantages over other reagents used: it reacts with amino acids and peptides under mild conditions, quickly and in high yield, producing easily removable and environmentally friendly by-products. The protecting t-butyloxycarbonyl group can then be removed under relatively mild hydrolytic or elimination conditions. The economic preparation of this agent is currently important both in terms of peptide hormone synthesis and in the context of new processes for the production of the synthetic peptide sweetener L-aspartic acid 1-L-phenylalanine hydrochloride dihydrate.

Several methods for the preparation of di-tert-butyl dicarbonate starting from an alkaline tert-butyl carbonate are known in the literature.

Pope et al. (M. M. Pope, Y. Yamamoto, DS Tarbell: Org. Syntheses 57, 45 (1977)) obtain by treatment with phosgene potassium tert-butyl carbonate di-tert-butyl carbonate which decarboxylates under catalysis 1,4-diazabicyclo (2). 2,2) octane to di-tert-butyl dicarbonate. The disadvantage of this procedure is the work with toxic phosgene and the use of hardly available 1,4-diazabicyclo (2,2,2) octane; other, simple amines, such as triethylamine, yield lower yields.

A series of works on the preparation of di-tert-butyl dicarbonate was published by Pozdnev et al. The essence of its synthesis is that the reaction of sodium tert-butyl carbonate with an acid chloride produces a mixed anhydride which reacts with an excess of sodium tert-butyl carbonate to di-tert-butyl dicarbonate. Good results were obtained with nitrobenzoic acid chlorides, the most preferred was trlchloroacetic acid chloride (VF Pozdnev, EA Smirnova, NN Podgornova, NK Zencova, U Kale: Z. Org. Chim. 15, 106 (1979): NN Podgornova, NK Zen cova, VF Pozdněv, UO Kálej: USSR AO 659 561). Of the inorganic acid chlorides, phosphorus oxychloride has been successful, but yields low yields due to the stoichiometric reaction (V. F. Pozdněv: 2. Obšč. Chim. 51, 421 (1981)). Although the by-product resulting from this synthesis can also be used to synthesize N-tert-butyloxycarbonylamino acids, its purification in the pure state is difficult.

For the preparation of di-tert-butyl dicarbonate, it is also advantageous to use also readily available and inexpensive p-toluenesulfo chloride or benzenesulfochloride. However, its reaction with alkaline tert-butyl carbonate in the presence of Ν, Ν-dimethylformamide is slow and, for satisfactory results, it is necessary to heat the reaction mixture at 70 ° C for 24 h (decomposition of the product already occurs at higher temperature). 845 and 247 846). However, this reaction rate is substantially increased by the addition of quaternary ammonium salts. The disadvantage of this process is its high sensitivity to the quality of the starting materials.

We have found that in the presence of pyridine the same reaction proceeds at room temperature with a yield of 43.7% of theory to p-toluenesulfochloride. However, the reaction time is long (70 h). Increasing the temperature to 40 ° C shortens it to 33 hours, but the yield drops to 13.9% of theory.

However, the reaction time is significantly reduced and the addition of so-called phase transfer catalysts ¹¹ increases the yield.

SUMMARY OF THE INVENTION The present invention relates to a reaction mixture comprising sodium tert-butyl carbonate, pyridine and an organic sulfoacid chloride of the formula II,

RSC ₂ C1 (II) wherein R is phenyl or p-tolyl, adds a quaternary ammonium salt of formula III,

R

X (III) wherein R 'is phenyl, benzyl or alkyl of 10 to 20 carbon atoms, R is alkyl of 1 to 4 carbon atoms and X 6 is an anion of a hydrohalic acid, thereby achieving a significant acceleration of the reaction.

In the process according to the invention, a solution of quaternary ammonium salt in pyridine is added to a stirred suspension of sodium tert-butyl carbonate in toluene at 20 to 70 ° C followed by a solution of p-toluenesulfochloride or benzenesulfochloride in toluene and the reaction mixture is heated to 20 to 70 ° C until the sulfochloric acid has reacted. The salts were removed by filtration and the product isolated by distillation.

It has been found that increasing the reaction temperature not only shortens the reaction time, but also increases the yield. An increase in the amount of quaternary ammonium salt added will also occur. For example, triethylbenzylammonium chloride (TEBA) or cetyltrimethylammonium chloride (Cetrimide) is suitable. However, the choice of catalysts to be used is not limited thereto.

The process according to the invention is fast, simple and saves both raw materials and energy.

The following examples illustrate but do not limit the generality of the process of the invention.

Example 1

To 100 g of a suspension of 0.10 mol of sodium tert-butyl carbonate in toluene was added with stirring a solution of 0.114 g (0.5 mmol) of TEBA in 10 ml of pyridine and a solution of 7.63 g (0.40 mol) of p-toluenesulfochloride in 30 ml. toluene. The reaction mixture was stirred for 6.3 h, stood for 15 h. Then it was filtered, the filter cake was washed with 100 ml of toluene. In the filtrate, 3.37 g (38.6% of theory on p-toluenesulfochloride) of di-tert-butyldicarbonate were found by IR spectroscopy.

Example 2

To 100 g of a suspension of 0.10 mol of sodium tert-butyl carbonate in toluene was added with stirring a solution of 0.228 g (1 mmol) of TEBA in 10 ml of pyridine and a solution of 7.63 g (0.40 mol) of p-toluenesulfochloride in 30 ml of toluene. The reaction mixture was heated to 50 ° C and maintained at this temperature. The reaction was complete after 1.5 h. After filtration and washing the filter cake with 100 ml of toluene, 7.41 g (84.9% of theory on p-toluenesulfochloride) of di-tert-butyl dicarbonate were found in the filtrate by iC spectroscopy.

Example 3

Analogous to Example 1, reaction temperature 40 ° C. The reaction was complete after 7 h. Yield of di-tert-butyl dicarbonate (determined by IR spectroscopy) 5.23 g (59.9% of theory on p-toluenesulfochloride). Fractional distillation gave 4.71 g of the product of b.p. 73-77 ° C / 200 Pa, 98-99 ° (GLC).

Example 4

Procedure analogous to Example 1, reaction temperature 50 ° C. The reaction was complete after 6 h. Yield of di-tert-butyl dicarbonate (determined by IR spectroscopy) 5.40 g (61.9% of theory on p-toluenesulfochloride). 4.83 g of product were obtained by distillation.

Example 5

Procedure analogous to Example 1, reaction temperature 60 ° C. The reaction was complete after 2 h. Yield of di-tert-butyl dicarbonate (determined by IR spectroscopy) 5.47 g (62.6% of theory on p-toluenesulfochloride).

Example6

Procedure analogous to Example 1, instead of TEBA, 0.182 g (0.5 mmol) of CETRIMID (cetyltrimethylammonium bromide) was used, reaction temperature 23 ° C. The reaction was complete after stirring for 16.4 h and standing for 80.5 h. Yield of di-tert-butyl dicarbonate (determined by iC spectroscopy) 5.35 g (61.2% of theory on p-toluenesulfochloride).

Example 7

A procedure analogous to Example 4, instead of p-toluenesulfochloride, was used in the same molar ratio benzenesulfochloride. After 6 h filtered, the salts washed with 100 mL toluene. 5.3 g of di-tert-butyldicarbonate (60.8% of theory for benzenesulfochloride) were found in the filtrate by iC spectroscopy.

Claims (2)

object of the invention A process for the preparation of di-tert-butyl dicarbonate of formula I (ch ₃ ) ₃ co-co-o-co-oc (ch ₃ ) ₃ (I) by reacting sodium tert-butyl carbonate with organic acid chlorides of formula II, R-SO ₂ Cl (II) wherein R is phenyl or p-tolyl, characterized in that the reaction is carried out in the presence of pyridine and catalyzed by a quaternary ammonium salt of the general formula III, X (III) R 1 -R, wherein R 1 is phenyl, benzyl or alkyl of 10 to 20 carbon atoms, R is alkyl of 1 to 4 carbon atoms, and X ^- is the anion of a hydrohalic acid. 2. Process according to claim 1, characterized in that the reaction is carried out at a temperature of 20 to 70 ° C. Severography, n. P., MOST